The development and validation of the Score for the Prediction of Postoperative Respiratory Complications (SPORC-2) to predict the requirement for early postoperative tracheal re-intubation: a hospital registry study

Postoperative pulmonary complications are associated with an increase in mortality, morbidity and healthcare utilisation. The Agency for Healthcare Research and Quality recommends risk assessment for postoperative respiratory complications in patients undergoing surgery. In this hospital registry study of adult patients undergoing non-cardiac surgery between 2005 and 2017 at two independent healthcare networks, a prediction instrument for early postoperative tracheal re-intubation was developed and externally validated. This was based on the development of the Score for Prediction Of Postoperative Respiratory Complications. For predictor selection, stepwise backward logistic regression and bootstrap resampling were applied. Development and validation cohorts were represented by 90,893 patients at Partners Healthcare and 67,046 patients at Beth Israel Deaconess Medical Center, of whom 699 (0.8%) and 587 (0.9%) patients, respectively, had their tracheas re-intubated. In addition to five pre-operative predictors identified in the Score for Prediction Of Postoperative Respiratory Complications, the final model included seven additional intra-operative predictors: early post-tracheal intubation desaturation; prolonged duration of surgery; high fraction of inspired oxygen; high vasopressor dose; blood transfusion; the absence of volatile anaesthetic use; and the absence of lung-protective ventilation. The area under the receiver operating characteristic curve for the new score was significantly greater than that of the original Score for Prediction Of Postoperative Respiratory Complications (0.84 [95%CI 0.82–0.85] vs. 0.76 [95%CI 0.75–0.78], respectively; p < 0.001). This may allow clinicians to develop and implement strategies to decrease the risk of early postoperative tracheal re-intubation.     

Brain serotonin transporter binding in non-depressed patients with Parkinson's disease

Early post-mortem data suggest that damage to brain serotonin neurones might play a role in some features (e.g., depression) of Parkinson's disease (PD). However, it is not known whether such damage is a typical characteristic of living patients with PD or whether the changes are regionally widespread. To address this question we measured, by positron emission tomography imaging, levels of the brain serotonin transporter (SERT), a marker for serotonin neurones, as inferred from binding of [¹¹C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB), a second generation SERT radioligand, in subcortical and cerebral cortical brain areas of clinically advanced non-depressed (confirmed by structured psychiatric interview) patients with PD. SERT binding levels in PD were lower than those in controls in all examined brain areas, with the changes statistically significant in orbitofrontal cortex (−22%), caudate (−30%), putamen (−26%), and midbrain (−29%). However, only a slight non-significant reduction (−7%) was observed in dorsolateral pre-frontal cortex, an area implicated in major depression. Our imaging data suggests that a modest, regionally widespread loss of brain serotonergic innervation might be a common feature of advanced PD. Further investigation will be required to establish whether SERT binding is more or less decreased in those patients with PD who also have major depressive disorder.     

Guidelines for Trials of Behavioral Treatments for Recurrent Headache, First Edition: American Headache Society Behavioral Clinical Trials Workgroup

Guidelines for design of clinical trials evaluating behavioral headache treatments were developed to facilitate production of quality research evaluating behavioral therapies for management of primary headache disorders. These guidelines were produced by a Workgroup of headache researchers under auspices of the American Headache Society. The guidelines are complementary to and modeled after guidelines for pharmacological trials published by the International Headache Society, but they address methodologic considerations unique to behavioral and other nonpharmacological treatments. Explicit guidelines for evaluating behavioral headache therapies are needed as the optimal methodology for behavioral (and other nonpharmacologic) trials necessarily differs from the preferred methodology for drug trials. In addition, trials comparing and integrating drug and behavioral therapies present methodological challenges not addressed by guidelines for pharmacologic research. These guidelines address patient selection, trial design for behavioral treatments and for comparisons across multiple treatment modalities (eg, behavioral vs pharmacologic), evaluation of results, and research ethics. Although developed specifically for behavioral therapies, the guidelines may apply to the design of clinical trials evaluating many forms of nonpharmacologic therapies for headache.     

Expression of a G-protein {beta} subunit-related gene during lymphocyte activation

Using a subtractlve strategy, we have cloned an activation-relatedgene from a human B cell cDNA library. Sequence analysis revealedthat this gene was identical to H12.3, a gene belonging to anexpanding family of guanlne nucleotlde-blndlng protein ßsubunlts. The expression of H12.3 was induclble in the latephase of mltogen-stlmulated T and B cells. In T cells, IL-2and IL-4 by themselves had no direct effect on the expressionof H12.3, but they could augment the level of steady-state H12.3mRNA stimulated by phytohemagglutlnln. On the other hand, IFN-and IL-6 had no obvious effect on the expression in B cellswith or without Staphytococcus aureus Cowan l-stlmulatlon. CyclosporinA, a strong immunosuppressant, Inhibited the mltogen-stlmulatedexpression of H12.3, but rapamycin, another such agent, didnot. In synchronized Jurkat cells, the expression of H12.3 hadno cell cycle-dependent decrease in S and G₂/M phase, whilecyclin E, which controls the progression of the cell cycle unlate G₁ phase, did show a periodic expression pattern. The resultssuggest that H12.3 might be involved in regulation of lymphocyteactivation.     

Tyrosine kinase-regulated small GTPase translocation and the activation of phospholipase D in HL60 granulocytes

We focus on the mechanisms of regulation of phospholipase D (PLD) activity. Three agonists known to stimulate PLD activity, fMet-Leu-Phe (fMLP), phorbol 12-myristate 13-acetate (PMA) and V4+-OOH, induced a differential translocation of ADP-ribosylation factor (ARF), RhoA, and protein kinase Calpha (PKCalpha), all cofactors for PLD activation. Whereas fMLP recruited all three proteins to membranes, V4+-OOH only elicited RhoA translocation and PMA induced ARF and PKCalpha translocation. Three tyrosine kinases inhibitors, ST-638, methyl 2,5-dihydroxycinnamate, and genistein reduced fMLP-stimulated PLD activity by up to 80%. Furthermore, tyrosine kinase inhibitors reduced the fMLP-induced increase of GTPgammaS-stimulated PLD activity in membranes and recruitment of ARF, RhoA, and PKCalpha to the membrane fraction. The data suggest that a tyrosine phosphorylation event is located upstream of the translocation of ARF, RhoA, and PKCalpha in the signaling pathway leading to PLD activation by fMLP. RO 31-8220, a specific inhibitor of PKC, reduced PMA-induced PLD activity by 80% in intact HL60 granulocytes but enhanced fMLP-stimulated PLD activity by 60%. Although PMA alone had no effect on RhoA recruitment to the membrane fraction, in the presence of RO 31-8220 the levels of membrane-bound RhoA were increased. The levels of membrane-bound ARF and PKCalpha were unaffected by RO 31-8220 during PMA stimulation. In contrast, fMLP-induced recruitment of ARF and RhoA was insensitive to RO 31-8220 but PKCalpha translocation was increased. We propose that RhoA translocation may be regulated by PKC in an ATP-independent manner. Furthermore, increased fMLP-induced PKCalpha translocation in the presence of RO 31-8220 may partially account for the synergistic activation of PLD observed when both fMLP and RO 31-8220 are used together in intact HL60 cells.     

Emergency treatment and long-term follow-up of posterior urethral valves

Posterior urethral valves have a broad spectrum of clinical severity determined by the degree and reversibility of the long stepwise sequence of secondary pathology. Neonatal azotemia and severe bilateral reflux are particularly important negative prognostic factors. In the mild cases, valve ablation with or without delayed reconstruction is good therapy. In the very severe cases, our interpretation of all the clinical and experimental information now available suggests that the time interval and the level of decompression are extremely important. Achievement of consistent low caliceal pressure without stasis and infections should be achieved as soon as possible. We do not agree with the philosophy of "valve ablation and wait and see" for secondary reconstruction as applied to the severe cases. An analogous philosophy would be treating all respiratory infections as upper respiratory infections and applying aggressive appropriate therapy for pneumonia only if the patient does not respond clinically. However, all controversy aside, the management of neonatal infants with posterior urethral valves remains a difficult and challenging problem for us all. The real challenge will be to improve published management results to the point that the family faced with decisions regarding an in utero diagnosis of posterior urethral valves will have enough hope to continue the pregnancy.     

Imaging of cAMP-specific phosphodiesterase-IV: comparison of [11C]rolipram and [11C]Ro 20-1724 in rats

The phosphodiesterase type IV (PDEIV) family of enzymes contributes to the metabolism of cAMP formed by the stimulation of beta-adrenergic, A2-adenosine, and H2-histamine receptors in the brain. Disturbances in cAMP-mediated signaling have been implicated in several neuropsychiatric disorders, and there is evidence that increasing cAMP levels through PDEIV inhibition improves the symptoms of these disorders. In the present study, the selective PDEIV inhibitors rolipram and Ro 20-1724, labeled with C-11, were evaluated in vivo in rats, as potential radioligands for imaging PDEIV enzymes with positron emission tomography (PET). Biodistribution experiments revealed a greater than threefold increased regional brain retention of [11C]rolipram as compared to [11C]Ro 20-1724. [nC]Rolipram uptake was higher in rat brain areas (e.g., cortical regions and olfactory system) showing higher expression of PDEIV enzymes, as determined previously using [3H]rolipram autoradiography or molecular genetic techniques. Binding of [n1C]rolipram and [11C]Ro 20-1724 was specific, since coadministration of high doses of unlabeled rolipram (10 mg/Kg, i.v.) or Ro 20-1724 (30 mg/Kg with [11C]rolipram and 10 mg/Kg with [11C]Ro 20-1724, i.v.) reduced radioactivity uptake in brain regions. Pretreatment with high doses of the PDEI selective inhibitor vinpocetine (10 mg/Kg, i.p., 15 min prior), or the noradrenaline reuptake inhibitor desipramine (10 mg/Kg, i.p., 30 min prior), or coinjection with the adenylyl cyclase activator forskolin (6.5 or 15 mg/Kg, i.v.), did not inhibit [11C]rolipram uptake in brain areas, suggesting binding selectivity for PDEIV enzymes. We conclude that [11C]rolipram, but not [11C]Ro 20-1724, is a promising radioligand for imaging the PDEIV enzymes with PET.     

Novelty and Familiarity Activations in PET Studies of Memory Encoding and Retrieval

Nine young right-handed men viewed colored pictures of people,scenes, and landscapes. Then, 24 hr later while undergoing PETscanning, they viewed previously studied (OLD) pictures in onetype of scan, and previously not seen (NEW) pictures in another.The OLD-NEW subtraction of PET images indicates familiarity,and the NEW-OLD indicates novelty. Familiarity activations,signalling aspects of retrieval, were observed in the left andright frontal areas, and posterior regions bilaterally. Noveltyactivations were in the right limbic regions, and bilaterallyin temporal and parietal regions, including area 37. These latteractivations were located similarly to novelty activations inprevious PET studies using visual words and auditory sentences,suggesting the existence of brain regions specializing in transmodalnovelty assessment The effects of novelty are seen both be haviorallyand in replicable patterns of cortical and subcortical activation.We propose a "novelty/encoding hypothesis": (1) novelty assessmentrepresents an early stage of long-term memory encoding; (2)elaborate, meaning-based encoding processes operate on the incoming information to the extent of its novelty, and therefore(3) the probability of long-term storage of information vanesdirectly with the novelty of the information.